title: Voltage-gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin-induced peripheral neurotoxicity: results from a prospective multicenter study.
abstract: BACKGROUND
  The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC).
  
  
  METHODS
  A total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes/no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative/chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%).
  
  
  RESULTS
  In the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC + TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P = .019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P = .023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P = .0029) and the occurrence of cumulative/chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P = .037).
  
  
  CONCLUSIONS
  The results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results.
authors.affiliation: Department of Neurology, "Saint Andrew's" General Hospital of Patras, Patras, Greece; Laboratory of Molecular Oncology, Division of Oncology, Department of Medicine, University Hospital of Patras, Rion-Patras, Greece.
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Argyriou
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Anna
authors.initials: A
authors.lastname: Antonacopoulou
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Chiara
authors.initials: C
authors.lastname: Briani
authors.forename: Jordi
authors.initials: J
authors.lastname: Bruna
authors.forename: Salvatore
authors.initials: S
authors.lastname: Terrazzino
authors.forename: Roser
authors.initials: R
authors.lastname: Velasco
authors.forename: Paola
authors.initials: P
authors.lastname: Alberti
authors.forename: Marta
authors.initials: M
authors.lastname: Campagnolo
authors.forename: Sara
authors.initials: S
authors.lastname: Lonardi
authors.forename: Diego
authors.initials: D
authors.lastname: Cortinovis
authors.forename: Marina
authors.initials: M
authors.lastname: Cazzaniga
authors.forename: Cristina
authors.initials: C
authors.lastname: Santos
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Psaromyalou
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Angelopoulou
authors.forename: Haralabos P
authors.initials: HP
authors.lastname: Kalofonos
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005838:Genotype; D006801:Humans; D015994:Incidence; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016896:Treatment Outcome; D061566:Voltage-Gated Sodium Channels / Q000235:genetics*
chemical_list: D009944:Organoplatinum Compounds; D061566:Voltage-Gated Sodium Channels; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil
keywords: SCNA; biomarkers; chemotherapy-induced peripheral neuropathy; genotyping; neurotoxicity; oxaliplatin